NaI-Mediated Acetamidosulfenylation of Alkenes with Bunte Salts as Thiolating Reagent Leading to β-Acetamido Sulfides

Article abstract of DOI:10.1055/s-0036-1588144

A direct and efficient method for the acetamidosulfenylation reaction of alkenes was developed, in which NaI was used as a catalyst, DMSO as the oxidant, nitriles as both the solvent and nucleophiles and stable, readily available Bunte salts as thiolating reagents. The reactions were carried out under mild conditions generating β-acetamido sulfides in good yields. Moreover, the reaction can be performed when alcohols are used as nucleophiles providing the corresponding β-alkoxysulfides in moderate yields, respectively.

Full text of DOI:10.1055/s-0036-1588144

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–F
letter
A
R. Zhang et al.
Letter
Synlett
NaI-Mediated Acetamidosulfenylation of Alkenes with Bunte Salts
as Thiolating Reagent Leading to β-Acetamido Sulfides
Rongxing Zhanga
O
Zhaohua Yana
HN
R2
S
R2CN
Dingyi Wanga
Yuanxing Wang*b
Sen Lin*a
Ar
R1
NaI
Ar
R1
SSO3Na
+
DMSO
R3
a College of Chemistry, Nanchang University, Nanchang,
Jiangxi 330031, P. R. of China
O
metal-free
R3OH
S
senlin@ncu.edu.cn
Ar
R1
b State Key Laboratory of Food Science and Technology,
Nanchang University, Nanchang, Jiangxi 330031, P. R.
of China
mlid reaction coditions
broad substrate scope
up to 87% yield
yuanxingwang@ncu.edu.cn
O
Received: 05.12.2016
Accepted after revision: 14.01.2017
Published online: 03.02.2017
OH
O
OH
O
NH
DOI: 10.1055/s-0036-1588144; Art ID: st-2016-w0819-l
COOH
O
S
OH
O
O
HOOC
HN
S
Abstract A direct and efficient method for the acetamidosulfenylation
reaction of alkenes was developed, in which NaI was used as a catalyst,
DMSO as the oxidant, nitriles as both the solvent and nucleophiles and
stable, readily available Bunte salts as thiolating reagents. The reactions
were carried out under mild conditions generating β-acetamido sul-
fides in good yields. Moreover, the reaction can be performed when al-
cohols are used as nucleophiles providing the corresponding β-alkoxy-
sulfides in moderate yields, respectively.
HN
COOH
O
Lactacystin
Frenolicin C
O
HN
COOH
S
Key words alkenes, Bunte salts, β-acetamido sulfides, nitriles, nucleo-
O
philes
O
O
O
O
H
Organosulfur compounds, over the past decades, not
only receive wide application in material science,1 but also
play an important role in medicinal chemistry,2 natural
products,3 and food chemistry.4 It is an effective strategy to
obtain organosulfur products through the difunctionaliza-
tion of alkenes in synthetic organic chemistry.5 Among
them, sulfenylation of alkene employing various sulfur re-
agents has gained great attention and progress in recent
years.6 Different sulfur sources, such as thiols,6a disulfides,6b
arylsulfonyl chlorides,6c and arylsulfonyl cyanides,6d etc.,6e
have been well developed for these transformations. How-
ever, in order to meet the requirements for multifunction-
alized organosulfur compounds, simpler, more effective,
and green methods for difunctionalization of alkenes are
still highly desirable.
O
COOH
H
H
OH
Lucencimycin D
Figure 1 Examples of β-acetamido sulfides
In the last years, the acetamidosulfenylation of alkene
has emerged as a direct and efficient protocol for the syn-
thesis of β-acetamido sulfides. Cui8a and Zheng,8b respec-
tively, described a three-component oxidative acetamido-
sulfenylation of alkenes in which disulfides and thiols with
unpleasant odor served as thiolating reagents (Scheme 1, a
and b).
Bunte salts, which can be prepared by the reaction of
sodium thiosulfate with various halides, are stable, readily
available, and odorless solid compounds.9 They have been
widely applied in the synthesis of organosulfur com-
pounds.10 In 2014, Reeves reported the synthesis of sulfides
via the reaction of Grignard reagent and Bunte salts.10a In
2015, Yi’s group described thia-Michael addition using
β-Acetamido sulfides, as an important member in sul-
fur-containing compounds, exist widely as moieties in nat-
ural products and biologically active molecules,7 such as
lactacystin,7a which is a proteasome inhibitor, frenolicin C7b
with anticoccidial activity, and lucensimycin D7c with anti-
bacterial activities (Figure 1).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

B
R. Zhang et al.
Letter
Synlett
mol%) as catalyst, DMSO (2.0 equiv) as oxidant, and nitriles
as both the solvent and nucleophiles at 100 °C in a sealed
tube.
Previous work:
O
O
HN
R1
R2
S
NaI
(a)
(b)
R2CN
R1
+
+
R3SSR3
+ R4CN
R3
Table 1 Optimization of Reaction Conditionsa
(NH4)2S2O8
O
HN
R1
R4
S
I2
R2
+
R3SH
R1
DMSO
HN
R3
S
R2
S
NaI, H2O
DMSO
+
+
MeCN
O
This work:
R1
SO3Na
HN
R3
S
NaI (20 mol%)
R2SSO3Na
Bunte salts
3a
1a
R3CN
2a
(c)
4a
+
+
DMSO (2.0 equiv)
R1
R2
Entry
Iodide (mol%)
Oxidant (equiv)
Temp (°C)
Yield (%)b
Scheme 1 Methods for acetamidosulfenylation of alkenes
1
2
I2 (20)
(NH4)2S2O8 (2.0)
(NH4)2S2O8 (2.0)
(NH4)2S2O8 (2.0)
(NH4)2S2O8 (2.0)
K2S2O8 (2.0)
TBHP(2.0)
80
80
n.r.
trace
58
TBAI (20)
NaI (20)
NH4I (20)
NaI (20)
NaI (20)
NaI (20)
NaI (20)
NaI (20)
I2 (10)
Bunte salts.10b Very recently, Luo10c and Ji,10d respectively,
explored the application of Bunte salts as thiolating regents
in the synthesis of 3-thioindoles. To the best of our knowl-
edge, Bunte salts have not yet been applied in the sulfenyla-
tion reaction of alkenes.
In consideration of the fact that the odorless and stable
Bunte salts can be easily converted into disulfides in sol-
vents, we envisioned that they should be better candidates
as thiolating sources for the acetamidosulfenylation of
alkenes. As a continuation of our project directed toward
the C–S bond formation, herein we present a direct and ef-
ficient method for the acetamidosulfenylation reaction of
alkenes in which NaI was used as a catalyst, DMSO as the
oxidant, nitriles as both the solvent and nucleophiles, and
Bunte salts as thiolating reagents (Scheme 1, c).
Initially, we conducted the reaction of styrene (1a, 0.30
mmol) with sodium s-benzyl thiosulfate (2a, 0.45 mmol) in
the presence of (NH4)2S2O8 and iodine in acetonitrile at
80 °C for nine hours (Table 1, entry 1), but no desired prod-
uct 4a was observed. It is worth noting that 4a was detect-
ed, respectively, in 56% and 58% yields when iodide salts
such as NH4I and NaI were used instead of iodine in acetoni-
trile as solvent (Table 1, entries 3 and 4). In order to im-
prove productivity, various oxidants for example K2S2O8,
TBHP, DTBP, DDQ, and DMSO were then screened, and re-
sults indicated that DMSO was the best choice and no reac-
tion took place when TBHP, DTBP, and DDQ were used as
oxidants (Scheme 2, entries 5–9). Next, the effect of reac-
tion temperature was explored (Table 1, entries 9–12). It
was found that the yield of 4a was improved to 84% when
the reaction temperature was increased to 100 °C (Table1,
entry 11). Decreasing the amount of DMSO led to a negative
effect and no reaction occurred without DMSO (Table 1, en-
tries 13 and 14). Similarly, the yield of 4a decreased when
reducing the loading of NaI, and the reaction did not take
place at all without NaI (Table 1, entries 15 and 16). Thus,
the optimized reaction conditions are as follows: alkenes
(1.0 equiv), Bunte salts (1.5 equiv), H2O (2.0 equiv), NaI (20
3
80
4
80
56
5
80
41
6
80
n.r.
n.r.
n.r.
75
7
DTBP (2.0)
80
8
DDQ (2.0)
80
9
DMSO (2.0)
DMSO (2.0)
DMSO (2.0)
DMSO (2.0)
DMSO (1.0)
–
80
10
11
12
13
14
15
16
80
47
NaI (20)
NaI (20)
NaI (20)
NaI (20)
NaI (10)
–
60
52
100
100
100
100
100
84
65
n.r.
74
DMSO (2.0)
DMSO (2.0)
n.r.
a Reaction conditions: 1a (0.30 mmol), 2a (0.45 mmol), 3a (1.5 mL), H2O
(0.60 mmol), 9 h in a sealed tube.
b Yield of isolated product.
Under the optimized reaction conditions, we investigat-
ed the scope and limitation of the reaction of sodium s-ben-
zylthiosulfate (2a) with various alkene substrates, and the
results are listed in Scheme 2. Styrenes having electron-rich
groups on the benzene ring such as 4-methyl and 4-tert-bu-
tyl gave the corresponding target products in good
yields(4b and 4c; Scheme 2). The reaction of styrenes pos-
sessing electron-withdrawing groups offered the corre-
sponding products in slightly poor 53–71% yields (4d–h;
Scheme 2). Notably, the reaction of cyclohexene as aliphatic
alkene with sodium s-benzyl thiosulfate (2a) also proceeds
well generating 4i in good yield (4i; Scheme 2).
Next, the participation of various Bunte salts and aryl
nitriles in this protocol were studied, and the results are
shown in Scheme 3. The use of sodium s-(4-methyl)benz-
ylthiosulfate and sodium s-benzylthiosulfates possessing
electron-poor groups on benzene ring resulted in the for-
mation of the corresponding β-acetamido sulfides in mod-
erate yields (5b–d; Scheme 3). The yield of products slightly
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

C
R. Zhang et al.
Letter
Synlett
O
NaI (20 mol%)
DMSO (2.0 equiv)
HN
S
MeCN
+
Ar
+
S
SO3Na
Ar
1
2a
3a
4
O
O
O
O
O
HN
HN
HN
HN
HN
S
S
S
S
S
F
Cl
4a, 84%
4b, 82%
4c, 75%
4d, 71%
4e, 64%
O
O
O
O
HN
HN
HN
Cl
S
HN
S
S
S
Br
Cl
4f, 53%
4g, 62%
4h, 70%
4i, 73%
Scheme 2 Reagents and conditions: 1 (0.30 mmol), 2a (0.45 mmol), 3a (1.5 mL), H2O (0.60 mmol), NaI (20 mol%), 9 h in a sealed tube. Yields are for
the isolated products.
decreased when aryl nitriles as nucleophiles were em-
ployed, which probably resulted from steric hindrance es-
pecially in the case of 5f (5e–g, Scheme 3). On the other
hand, sodium s-arylthiosulfate possessing 4-methyl on the
benzene ring was used in reaction with good yield (5h;
Scheme 3), similarly, sodium s-(4-chloro)phenylthiosulfate
underwent the same acetamidosulfenylation reaction with
the formation of 5i in 62% yield (5i; Scheme 3) which may
be influenced by electron-poor effect. Moreover, aliphatic
Bunte salt can partcipate in the reaction with good yield
(5j; Scheme 3).
Furthermore, the potential industrial application of this
reaction was demonstrated on a gram scale. As shown in
Scheme 4, the reaction could afford 1.62 grams of 4a in 71%
yield, demonstrating the potential applications of the reac-
tion for a large-scale synthesis of β-acetamido sulfides.
O
HN
R2
S
NaI (20 mol%)
R1SSO3Na
R2CN
+
+
R1
DMSO (2.0 equiv)
1a
2
3
5
O
O
O
F
Cl
HN
HN
HN
HN
O
HN
O
S
S
S
S
S
5b, 63%
5c, 65%
5d, 71%
5e, 81%
5f, 63%
O
O
O
HN
HN
HN
HN
O
S
S
S
S
Cl
5g, 72%
5h, 87%
5i, 62%
5j, 80%
Scheme 3 Reagents and conditions: 1a (0.30 mmol), 2 (0.45 mmol), 3 (1.5 mL), H2O (0.60 mmol), NaI (20 mol%), 9 h in a sealed tube. Yields are for the
isolated products.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

D
R. Zhang et al.
Letter
Synlett
O
HN
NaI (20 mol%)
S
S
DMSO (2.0 equiv)
+
+
MeCN
3a (12 mL)
SO3Na
H2O (0.5 mL)
100 °C, 9 h
2a (12 mmol)
1a (8 mmol)
4a (71%, 1.62 g)
Scheme 4 Gram-scale reaction
R
O
NaI (20 mol%)
MeCN (1.5 mL)
S
S
+
ROH
+
SO3Na
DMSO (2.0 equiv)
6
1a
2a
7
O
O
S
S
O
S
7a, 42%
7c, 31%
7b, 50%
Scheme 5 Reagents and conditions: 1a (0.30 mmol), 2 (0.45 mmol), 6 (100 μL), H2O (0.60 mmol), NaI (20 mol%), 9 h in air. Yields are for the isolated
products.
To extend the scope of sulfenylation of alkenes with
Bunte salts as thiolating reagent, we tested other nucleop-
hiles. The reactions of sodium s-benzyl thiosulfate (2a)
with styrene (1a) and alcohols 6 were carried out, and the
results are shown in Scheme 5. The results show that the
alkoxysulfenylation of styrene can proceed well although
β-alkoxy sulfides were only obtained in moderate yields.
In order to attain further insight into the reaction mech-
anism, we tried three reactions as contents of control ex-
periments, and the results are outlined in Scheme 4. First,
the reaction of 1a with 2a in the presence of 2,6-di-tert-bu-
tylphenol as free-radical inhibitor was not terminated and
it still proceeds smoothly (Scheme 6, eq. 1). Sodium s-ben-
zyl sulfothioate (2a) can be successfully transformed into
dibenzyl disulfide (8a) in 95% yield under the standard con-
ditions in the absence of NaI and DMSO (Scheme 6, eq. 2).
No corresponding products were observed when sodium s-
benzyl sulfothioate (2a) was replaced by dibenzyl disulfide
(8a, Scheme 6, eq. 3).The above results show that the reac-
tion mechanism of 1a with 2a might not be a radical path-
way, and the disulfide might be an intermediate.
O
HN
S
NaI (20 mol%)
DMSO (2.0 equiv)
S
(1)
+
SO3Na
BHT (2.0 equiv)
100 °C, 9 h
1a, 0.30 mmol
4a, 82%
2a, 0.45 mmol
S
MeCN (1.5 mL)
100 °C, 9 h
S
(2)
S
SO3Na
2a, 0.45 mmol
8a, 95%
O
HN
S
S
NaI (10 mol%)
S
(3)
+
DMSO (2.0 equiv)
100 °C, 9 h
1a, 0.30 mmol
8a, 0.23 mmol
4a, 0%
Scheme 6 Control experiments
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

E
R. Zhang et al.
Letter
Synlett
On the basis of the reported literatures8,11–14 and the
above results of control experiments, a plausible mecha-
nism is depicted in Scheme 7. Under the heating conditions,
the hydrolysis of Bunte salts A in the presence of water
leads to the formation of species bisulfate anion and thiol or
thiol anion B in the reaction mixture.11 The disulfide C are
thus generated through the attack by thiol or thiol anion B
on another Bunte salt A.12 Next, the reaction of disulfide C
with I2 to gives RSI D which is an electrophilic species,13a
and an intermediate F appeared via the attack of alkene E
by RSI D.8a,13b The subsequent reaction of the intermediate F
with nitriles followed by Ritter reaction, alcohol affords β-
acetamido sulfides G, and β-alkoxy sulfides I with the re-
lease of HI.14 Finally, two molecules of HI were oxidized by
DMSO and transformed into molecular I2 accompanied by
the formation of water and dimethyl sulfide.13a,15
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588144.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
References and Notes
(1) (a) Cook, S.; Furube, A.; Katoh, R. J. Mater. Chem. 2012, 22, 4282.
(b) Manthiram, A.; Fu, Y. Z.; Chung, S. H.; Zu, C.; Su, Y. S. Chem.
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N.; Buyukcakir, O.; Kim, H. J.; Yu, J. S.; Woo, S. G.; Jang, M. C.;
Son, B. K.; Coskun, A.; Choi, J. W. ACS Energy Lett. 2016, 1, 566.
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Meanwell, N. A. J. Med. Chem. 2015, 58, 4383. (b) Dahlin, J. L.;
Nissink, J. M.; Strasser, J. M.; Francis, S.; Higgins, L. A.; Zhou, H.;
Zhang, Z. G.; Walters, M. A. J. Med. Chem. 2015, 58, 2091.
(c) Kardos, J.; Szabo, Z.; Heja, L. J. Med. Chem. 2016, 59, 777.
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Prod. 2015, 78, 1904. (c) Hill, R.; Sutherland, A. Nat. Prod. Rep.
2016, 33, 122.
RSSO3Na
A
(4) (a) Wakamatsu, J.; Stark, T. D.; Hofmann, T. J. Agric. Food Chem.
2016, 64, 5845. (b) Williams, K. L.; Tjeerdema, R. S. J. Agric. Food
Chem. 2016, 64, 4838.
(5) (a) Jensen, K. H.; Webb, J. D.; Sigman, M. S. J. Am. Chem. Soc.
2010, 132, 17471. (b) Ricci, P.; Khotavivattana, T.; Pfeifer, L.;
Médebielle, M.; Morphy, J. R.; Gouverneur, V. Chem. Sci. 2017, 8,
1195.
H2O
RSH
or
+
RSSR
C
RSSO3Na
RS
A
B
HSO4
2
NaI
DMS + H2O
SO3
OH
S
DMSO
I2
HI
I
I
(6) (a) Fang, Z. S.; Qiang, P. X.; Hao, Z.; Adedamola, S.; Ping, Z. J. J.
Org. Chem. 2015, 7, 3682. (b) Vieira, A. A.; Azeredo, J. B.; Godoi,
M.; Santi, C.; Junior, E. N. S.; Braga, A. L. J. Org. Chem. 2015, 80,
2120. (c) Wang, D. Y.; Zhang, R. X.; Lin, S.; Yan, Z. H.; Guo, S. M.
Synlett 2016, 27, 2003. (d) Yang, F. L.; Wang, F. X.; Wang, T. T.;
Wang, Y. J.; Tian, S. K. Chem. Commun. 2014, 17, 2111. (e) Wei,
W.; Wen, J. W.; Yang, D. S.; Wu, M.; You, J. M.; Wang, H. Org.
Biomol. Chem. 2014, 39, 7678.
HI
O
R
HN
S
RSI
D
I
S
Ar
RCN + H2O
Ar
R
Ritter reaction
F
G
Ar
R1OH
E
(7) (a) Gu, W. X.; Silverman, R. B. J. Org. Chem. 2011, 76, 8287.
(b) Wang, X. C.; Shaaban, K. A.; Elshahawi, S. I.; Ponomareva, L.
V.; Sunkara, M.; Zhang, Y. N.; Copley, G. C.; Hower, J. C.; Morris,
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Prod. 2009, 72, 345.
OR1
S
R
Ar
I
Scheme 7 Plausible reaction mechanism
(8) (a) Cui, H. H.; Liu, X. X.; Wei, W.; Yang, D. S.; He, C. L.; Zhang, T.
T.; Wang, H. J. Org. Chem. 2016, 81, 2252. (b) Zheng, Y.; He, Y.;
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A.; Senanayake, C. H. Org. Lett. 2014, 16, 1196. (b) Ding, Y. C.;
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J. Org. Biomol. Chem. 2016, 14, 9384.
In summary, a direct and facile method has been devel-
oped for the synthesis of β-acetamido sulfides through the
acetamidosulfenyation of alkenes in moderate to good
yields in which odorless solid Bunte salts were used as thio-
lating reagents, NaI as a catalyst, DMSO as the mild oxidant,
and nitriles as both the solvent and nucleophiles.16 Further-
more, the reaction can be extended for alcohols substrate
leading to the synthesis of β-alkoxy sulfides, respectively.
(11) Abbasi, M.; Mohammadizadeh, M. R.; Saeedi, N. New J. Chem.
2016, 40, 89.
Acknowledgment
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We are grateful for the financial support from the National Natural
Science Foundation of China (21302084).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

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(16) General Procedure for the Synthesis of Compound 4 or 5
NaI (0.06 mmol), H2O (0.60 mmol) and Bunte salt 2 (0.45 mmol)
were added to a solution of nitrile 3 containing alkene 1 (0.30
mmol), followed by the addition of DMSO (0.60 mmol). The
reaction mixture was stirred in a sealed tube at 100 °C for 9 h.
After completion of the reaction, the reaction mixture was
diluted with EtOAc, and quenched with sat. Na2S2O3 solution
and extracted with EtOAc (3 × 10 mL). The organic layer was
washed with water and dried over anhydrous Na2SO4. The
solvent was evaporated in vacuo, and the residue was subjected
to column chromatography using EtOAc in PE as the eluent to
afford the pure target product 4 or 5.
(100 MHz, CDCl3): δ = 169.5, 138.0, 137.7, 137.4, 129.4, 129.0,
128.5, 127.1, 125.4, 51.8, 37.1, 36.4, 23.4, 21.1. ESI-HRMS: m/z
calcd for C18H21NOS [M + Cl]+: 334.1027; found: 334.1036.
General Procedure for the Synthesis of Compound 7
NaI (0.06 mmol) and 2a (0.45 mmol) was added to a solution of
acetonitrile 3a containing styrene 1a (0.30 mmol) and alcohol
(100 μL) or 2-allylphenol 6d (0.3 mmol), followed by DMSO
(0.60 mmol). The reaction mixture was stirred at 90 °C for 6–9
h. After completion of the reaction, the reaction mixture was
diluted with EtOAc, quenched with sat. Na2S2O3 solution and
extracted twice with EtOAc (2 × 15 mL). The organic layer was
washed with water and dried over anhydrous Na2SO4. The
solvent was evaporated in vacuo, and the residue was subjected
to column chromatography using EtOAc in PE as the eluent to
afford the pure target product 7.Compound 7a was obtained in
42% yield (32.7 mg) according to the general procedure for the
synthesis of 7 as a colorless liquid. 1H NMR (400 MHz, CDCl3): δ
= 7.37–7.21 (m, 10 H), 4.31 (q, J = 8.0 Hz, 1 H), 3.69 (q, J = 12.0
Hz, 1 H), 3.42–3.33 (m, 1 H), 2.84 (q, J = 8.0 Hz, 1 H), 2.60 (q, J =
8.0 Hz, 1 H), 1.20 (t, J =8.0 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ
= 141.6, 138.6, 129.0, 129.4, 128.4, 128.4, 127.8, 126.9, 126.7,
82.3, 64.5, 38.7, 37.2, 15.3. ESI-HRMS: m/z calcd for C17H20OS
[M + Na]+: 295.1127; found: 295.1120.
Compound 4b was obtained in 82% yield (73.7 mg) according to
the general procedure for the synthesis of 4 as a white solid. 1H
NMR (400 MHz, CDCl3): δ = 7.32–7.23 (m, 5 H), 7.12 (s, 4 H),
6.03 (d, J = 8.0 Hz, 1 H), 5.12 (q, J = 8.0 Hz, 1 H), 3.59 (q, J = 12 Hz,
2 H), 2.86–2.74 (m, 2 H), 2.32 (s, 3 H), 1.95 (s, 3 H). 13C NMR
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F